Many complex oligosaccharides on the cell surface are fucosylate (Varki, A. Glycobiology 1993, 3, 97-130; Hakomori et al. Adv. Cancer Res. 1989, 52, 257; Hakomori et al. J. Biol. Chem. 1984, 259, 4672; Feizi, T. Nature, 1985, 314, 53). These fucose containing structures are involved in cell-cell interactions which mediate inflammation, tumor development, and blood clotting (Ichikawa et al. 1994, Chem. Br. 117; Parekh et al. TIBTECH, 1994, 12, 339). The biosynthesis of these structures requires the action of several glycosyltransferases, of which fucosylation by a class of fucosyltransferases (FucT) is the last and critical step (Natsuka et al. Curr. Opin. Struct. Biol. 1994, 4, 683; Holme et al. J. Biol. Chem. 1986, 261, 3737; Kornfeld et al. Annu. Rev. Biochem. 1985, 54, 631-664). Therefore inhibitors of FucT are potentially useful as anti-inflammatory and anti-tumor drugs. To date only limited success has been achieved in the development of potent inhibitors of this important class of enzymes. Besides the production of unreactive analogs of GDP-fucose (Cai et al. J. Org. Chem. 1992, 57, 6693; Luengo et al. Tetrahedron Lett. 1992, 33, 6911) a bisubstrate inhibitor for .alpha.-1,2-fucosyltransferase has also been reported (Palcic et al. J. Biol. Chem. 1989, 264, 17174). Very recently, we and others have synthesized trisubstrate analogs, of .alpha.-1,3-fucosyltransferase (Heskamp et al. Tetrahedron, 1995, 51, 8397; Heskamp et al. J. Carbohydr. Chem. 1995, 14, 1265; Qiao et al. J. Am. Chem. Soc. 1996, 118, 7653). Although FucT V has been shown to have a catalytic residue with pKa=4.1, presumably an active site carboxylate, it has never been considered in the design of inhibitors until recently (Murray et al. Biochemistry, 1996, 34, 11183). Product inhibition studies with human .alpha.-1,3-fucosyltransferase (FucT V) have been used to establish that FucT V has an ordered, sequential, bi-bi mechanism with guanosine 5'-diphospho-.beta.-1-fucose (GDP-Fuc) binding first and the product releasing last (Qiao et al. J. Am. Chem. Soc. 1996, 118, 7653; Murray et al. Biochemistry, 1997, 36, 823). Our past approach to the construction of fucosyltransferase inhibitors has been based on mimicking the proposed transition state by covalently linking an iminocyclitol to the 3-position of the acceptor substrate. Besides the fact the trisaccharide should form a complex with GDP and provide synergistic inhibition, it is assumed that a basic two carbon spacer could block the catalytic residue and improve the inhibition by additional hydrogen bonding (For synergistic inhibition see: (Wong et al. J. Am. Chem. Soc. 1992, 114, 7321; Ichikawa et al. J. Am. Chem. Soc. 1992, 114, 9283).
What is needed are improved fucosyltransferase inhibitors. Furthermore, what is needed is an efficient and general method for the synthesis of improved fucosyltransferase inhibitors.